| Background and Objectives: To provide postoperative analgesia, the anesthesiologist has at his disposal a panel of different medications and also regional techniques of neural blockade. Loco-regional analgesia (central or peripheral) blocks conduction of painful influx to the central nervous system by the use of local anesthetics (LA). Among these drugs, ropivacaine (ROP), has an enormous potential given is long-acting efficacy and low incidence of toxicity. Currently, ROP is not licensed for use in spinal anesthesia (central block) in all countries due to a lack of data from controlled clinical trials. So far, research efforts on this topic have mainly focused on safety and dose-finding issues. In addition, the most appropriate dose for a peripheral nerve block has never been estimated empirically. Dosing recommendation for LAs should be site-specific and adapted to the intensity of the stimuli produced by a surgery and to the duration of analgesia required. Ultimately, these should guide clinicians in identifying the most appropriate block for the individual patients by taking into account demographic factors that may affect the pharmacokinetics (PK) and pharmacodynamics (PD) of LA overall objective of the current research).;Analytical Method Validation Manuscript 1: First, a specific and sensitive assay has been developed and validated for the determination of ROP in human plasma.;Biomarker Validation Manuscript 2: Second, the reliability of a neurostimulator measuring current perception threshold (CPT) was assessed in healthy volunteers. The device uses a constant transcutaneous electrical sine wave stimulus at different frequencies specific to pain-conducting fibers. Our results suggest that CPT are reliable and can be applied to characterize, in a quantitative manner, the sensory onset of a peripheral nerve block in a clinical setting.;Clinical Studies Manuscript 3: The systemic absorption of ROP after a femoral nerve block in orthopedic patients was then characterized using extended rich PK-sampling, i.e. up to 4 days post-dosing. Our model used for data analysis confirms that, in a similar manner to neuraxial sites of LAs injection, the systemic absorption of ROP from the femoral space is biphasic, i.e. a rapid initial phase (mean absorption time of 25 min, % CI: 19 -- 38 min) followed by a much slower phase (half-life (T1/2) of 3.9 h, % CI: 2.9 -- 6.0 h). A significant age-related increase in the permeability of the LA was also observed in our elderly patients (n = 19, age = 62.6 +/- 7.1 yr).;Manuscript 4: A population PK-PD analysis of the sensory anesthesia (CPT) of ROP using our PK model was also performed. The effect-site amount producing 90% of the maximum possible effect (AE90) was estimated as 20.2 +/- 10.1 mg. At 2 x AE90, the sigmoid E max model predicted an onset time of 23.4 +/- 12.5 min and a duration of 22.9 +/- 5.3 h. To the best of our knowledge, this is the first PK-PD model developed for a peripheral nerve block.;Manuscript 5: In the third and last study, a similar approach was used to characterise the PK-PD relationship of intrathecally administered ROP in patients undergoing minor lower limb surgery. The biphasic release of the agent from the intrathecal space was modeled using a rapid initial absorption phase (T1/2 of 49 min, % CI: 24 -- 77 min) followed (lag-time of ∼ 18 +/- 2 min) by a slightly slower input rate (T1/2 of 66 min, % CI: 36 -- 97 min). ROP maximal response was observed within 12.6 +/- 4.9 min of dosing, with a subsequent return to baseline 210 +/- 55 min after the administration of the LA. The effect-site amount producing 50 % of the Emax (AE50) was estimated at 7.3 +/- 2.3 mg.;Conclusion: Altogether, the proposed models can be used to predict the time-course of sensory blockade after a femoral nerve block and spinal anesthesia using ROP and to optimize dosing regimen according to clinical needs with regard to important cofactors such as age. |
